PHYSIOLOGY’S IMPACT
Maël Lemoine* and Thomas Pradeu*
ImmunoConcept, UMR5164, CNRS & University of Bordeaux,
Bordeaux, France
Dissecting the Meanings of “Physiology” to
Assess the Vitality of the Discipline
Introduction
Physiology is one of the central disci-
plines on which all biological and medical
sciences were historically built (63). How-
ever, questions have recently been raised
concerning the relevance and vitality of
physiology and its ability to make a useful
contribution to biological and medical
sciences. Physiology is sometimes seen as
a discipline of the past that is “dying” in
the era of molecular biology and high-
throughput DNA sequencing (5, 50, 77,
96). However, close scrutiny would sug-
gest a less clear-cut picture. Not everyone
would agree with claims that the intellec-
tual discipline of physiology is dying, or
perhaps even already dead (97). They feel
that physiology has gradually “disinte-
grated” precisely because it has given rise
to a series of daughter disciplines, such
as neurosciences, immunology, and en-
docrinology (45, 74, 84). According to
this view, physiology is not so much
“dead” as a key element underlying
some of the most dynamic fields in the
biological sciences of today, including
the various -omics disciplines (120).
Some would even defend the view that
physiology remains a key field in mod-
ern-day biology and that it could per-
haps inspire renewal in other biological
disciplines, including molecular biology
and evolution (24, 51, 84, 86).
This conceptual review aims to intro-
duce physiologists to the philosophy of
biology and medicine. We argue here that
the claims made about the vitality and
utility of physiology depend heavily on
the definition of “physiology” adopted.
We distinguish between two families of
definitions of physiology found in the sci-
entific literature. Some focus on what
physiology is about—its object—whereas
others focus on how physiology is used to
study the biological reality—its method.
Within each definition, we will examine
*M. Lemoine and T. Pradeu contributed
equally to this work.
236
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Published June 6, 2018; doi:10.1152/physiol.00015.2018
the claims about the vitality of physiol-
ogy. We will consider the specific features
of physiology and whether it can continue
to play the integrative role it has played in
the past, with the capacity to unify diverse
biological approaches and experimental
data through common concepts or ex-
planatory principles. The results of this
conceptual investigation are shown in Ta-
ble 1.
In a nutshell, physiology can be viewed
from two different angles. If we use a line of
reasoning according to which each biolog-
ical science provides its own contribution
to the general functional explanation, then
physiology now coexists with other disci-
plines. On the other hand, as a science with
a specific object, the normal state of the
whole organism, characterized by homeo-
stasis, physiology is constantly reinventing
itself and will continue to make a crucial
contribution to other disciplines.
What is Physiology? Lessons
from the Historical
Development of a Discipline
Physiology has very deep, rich historical
roots providing important insight into the
current status of this discipline. A quick
glance at the history of physiology high-
lights three key debates:
1) Is physiology a general all-encom-
passing biological science, or, much
more modestly, simply the medical
investigation of the functions of hu-
man organs?
2) Can a single, highly general phe-
nomenon, such as homeostasis,
serve as the basis for integrating
knowledge about organisms?
3) Can physiology be identified with a
specific experimental method?
The first of these debates concerns the
status of physiology as either the broadest
biological science or, much more humbly,
a domain focusing primarily on humans
and their health. Physiology has a long
history. It has often been stressed that the
roots of physiology lie in the works of
1548-9213/18 Copyright © 2018 Int. Union Physiol. Sci./Am. Physiol. Soc.
PHYSIOLOGY 33: 236 –245, 2018.
Aristotle and Galen, and the term physi-
ology was first coined by the French phy-
sician Jean Fernel in his De Naturali Parte
Medicinae in 1542 (34). However, the
meaning of physiology has changed sig-
nificantly during the course of the history
of this domain. In the 18th century, in
particular, physiology had a broad, not
specifically medical sense, encompassing
animals and plants, very much like the
modern term “biology” (114). This tradi-
tion culminated at the start of the 19th
century with Dutrochet’s claim of the
unification of the general science of phys-
iology around phenomena such as osmo-
sis (1). At around the same time, Schwann
generalized the notion of metabolism,
and both of these scientists promoted the
idea of cellular physiology as a funda-
mental biological science applicable to all
living things (28). Cuvier, through his
conception of comparative anatomy
based on functional correlations between
organs, also contributed to this idea of a
broad science (3), and “comparative
physiology” developed in parallel with
“comparative anatomy.” However, the
term physiology has also been used in a
more restricted, medical, and human-
centered sense (22, 23), which has also
undergone major shifts in meaning. Phys-
iology was long considered a branch of
anatomy (54), particularly at the institu-
tional level, but also, to a lesser extent,
intellectually. However, in the 18th and
19th centuries, physiologists began to
show that function could not necessarily
be deduced from structure (13), thereby
relegating anatomy to an ancillary role
(63, 114). This development led to a large
number of physiology laboratories, de-
partments, and societies being created in
a general movement of liberation from
both the anatomical and medical con-
texts. This debate about the object of
physiology and its degree of generality
(i.e., is its object limited to human health,
or much more broadly, the entire living
world?) is still alive today.
The second debate concerns the possi-
bility of using a single phenomenon as
the unifying basis of physiology in gen-
eral. Historically, physiologists endowed
various phenomena with a central ex-
planatory power in the general science of
Table 1. An examination of the most frequent definitions of the discipline of ‘physiology’ in the scientific literature
Definition of Physiology in the
Literature Explication of This Definition Is Physiology Alive in This Sense?
Method
Physiology is the science of functions Physiology focuses on identifying the causal Alive but complemented by emerging
contribution of a part to the whole biological disciplines not based on
organism. the explanation of biological
phenomena through the assignment
of causal roles.
Physiology is the main explanatory In this view, many life sciences are Alive but complemented by emerging
domain of the biological sciences descriptive, but physiology is distinctive in biological disciplines that do not
that it aims to provide explanations of provide explanations.
biological phenomena.
Physiology is the basic science of In this view, biological data become Alive since physiology is indeed a
organisms intelligible only after their integration into a basic science based on a template of
physiological framework. multiple layers of functions, but it is
not necessarily the basic science in
organism biology.
Object
Physiology as the science of Insofar as it includes pathophysiology, Alive and necessary, but not sufficient
physiological and pathological physiology can be defined as the science of to explain how physiological
phenomena healthy and pathological phenomena. phenomena become pathological
Physiology as the science of the This definition is understood in at least two Alive, but often vague. Physiological
integrity of the organism senses:1) Physiology takes into account the integration (in a hierarchy of
organism as a whole when considering embedded functions) must be
biological phenomena.2) Physiology complemented by other forms of
investigates the role played by “unifying integration. The nervous and immune
systems”—particularly the nervous and systems are endowed with the
immune systems—in the integrity of the capacity to unify the organism into a
organism. cohesive whole.
Physiology as the science of a highly Physiology has focused on phenomena Alive but requiring complementation
general, almost universal, biological observable at all levels in all living beings, when the identification of interactions
process: the case of homeostasis including homeostasis in particular. between physiological systems leads
to the search for non-physiological
explanations. Alive and fruitful when a
homeostasis-based reasoning leads to
the discovery of novel, “cross-
system,” physiological phenomenon.
Since it would be impossible to investigate systematically all published definitions of physiology, we tried to group together consensual and
common views (left), especially in the context of the alleged crisis in physiology. We then used the philosophical method of conceptual
analysis, or “explication,” to explain what these definitions refer to (middle). Finally, we propose a critical assessment of these definitions
in terms of the vitality of physiology in modern science (right). One of the results of our analysis was the distinction between object-based
(bottom) and method-based (top) definitions of physiology.

organisms. In the 18th century, living or-
ganisms were characterized by integrated
mechanisms, systemic properties, or
what was then called “living economy”
and later became “animal economy”
(114). This aspect was seen as the specific
object of physiology at the beginning of the
19th century. By focusing on how organ-
isms become autonomous with respect to
variations of their environment, Claude
Bernard defined the milieu intérieur, a ba-
sic phenomenon in every organism (6).
Cannon stressed the importance of a dy-
namic equilibrium between essential
parameters, which he referred to as homeo-
stasis (15). These different views have in
common the idea that it is possible to
unify physiological processes under the
banner of a single fundamental phe-
nomenon of life. Again, as we will see
below, many modern physiologists
continue to share this ambition for their
discipline (108).
The third debate concerns the possibil-
ity of identifying physiology with a spe-
cific experimental method. Physiology
became a fully fledged experimental sci-
ence in the second half of the 19th cen-
tury. At the time, physiology was firmly
entrenched in a hypothesis-driven ap-
proach, promoted, in particular, by
Claude Bernard (6, 8), considered by
many to be the “founder” of experimental
physiology (29, 43, 82), although other pi-
oneers preceded him (42). One key ques-
tion concerns the extent to which
physiology can be identified with the use
of what were then new, cutting-edge, spe-
cific detection and intervention tech-
niques, such as electrophysiology or
experimental lesions, as in the work of
François Magendie, Johannes Müller,
Claude Bernard, Herman von Helmoltz,
Ivan Pavlov, and Charles Sherrington
(63). Were the continual, rapid changes in
technology accompanied by changes in
physiology? Or did physiology remain as-
sociated with technologies invented at

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the end of the 19th and beginning of the
20th centuries? The influence of new ex-
perimental tools, transforming the field of
physiology, continues to be a matter of
debate for the physiologists of today (98).
The definition of the discipline of phys-
iology and estimations of its current rel-
evance depend very much on which of
these historical debates is considered the
most important. Evaluation of the status
of physiology in modern life sciences de-
pends heavily on, for example, whether
physiology is still seen as an all-encom-
passing discipline, whether it is seen as
associated with a general phenomenon,
such as homeostasis, or whether it is con-
sidered to be based on the use of specific
experimental methods, such as electro-
physiology. These different standpoints
make it difficult to propose a general
characterization of physiology, and at
least some of the disagreements concern-
ing the vitality of this discipline arise from
the different conceptions of physiology
held by different researchers.
Despite these uncertainties, history
suggests that a possible overall definition
of physiology can be devised from its
method and object (Table 2; see also Table
1). Such a definition would probably also
be representative of the views of contem-
porary physiologists concerning their
discipline. Methodologically speaking,
physiology is explanatory, its explana-
tions are of a functional kind, and it is
integrative. Thematically, it focuses on
phenomena considered normal or patho-
logical, on the integrity of organisms or on
general phenomena common to many
or even all living things, such as
homeostasis.
Below, we provide a detailed justifica-
tion of this characterization of physiology
in terms of its method and object, and we
show that the current vitality of physiol-
ogy can be assessed with reference to this
classification.
Physiological Methods
In this section, we show that the primor-
dial goal of physiology is explaining a sys-
tem’s behavior, rather than predicting or
controlling it, and that the explanations
provided are based on function. Some re-
cent, innovative approaches have di-
verged from this rationale of explanation
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based on function. It remains unclear
whether these approaches should be seen
as offshoots of physiology or of other dis-
ciplines. As we shall see, those inclined to
see them as offshoots of physiology tend
to view physiology as an integrative sci-
ence, at the risk of reducing it to a syn-
thesis of preexisting knowledge rather
than a source of new knowledge.
In this examination of the methods of
physiology, we will begin by considering
why attempts to explain phenomena on
the basis of biological functions play such
a key role in physiological science. We
will then show that the relevance of
physiology has been called into ques-
tion precisely because emerging biolog-
ical disciplines either do not explain
biological phenomena in terms of func-
tion or do not explain them at all. Fi-
nally, we examine the claim, often made
by physiologists themselves, that phys-
iological methods remain the best way
to integrate biological knowledge.
The Central Role of Function in
Physiology
One hallmark of physiology is its search for
functional explanations. The identification
of functions through their experimental
neutralization provides information about
the contribution of part of the organism to
the whole, and an explanation of this
function:
“Successful physiological analysis re-
quires an understanding of the func-
tional interactions between the key
components of cells, organs, and sys-
tems, as well as how these interactions
change in disease states” (79).
“Physiology, in my view, is clearly char-
acterized by asking the truly functional
questions. These questions can only be
answered by continuously integrating
knowledge from other disciplines into
the larger scheme of mechanisms that
allow organisms to actually live” (97).
Philosophers of science have character-
ized “functional analysis” as the decom-
position of a causal role of part of a
system into a flowchart of functions (21).
Functional analyses generally consider
one of the effects or outputs of a system.
They consider the causal interactions be-
tween parts, called “functions,” relative to
the effect of interest. Each of these inter-
actions can, in turn, be broken down into
causal interactions between subparts.
The result is an explanation. There is
some debate among philosophers of biol-
ogy and medicine as to whether this is
sufficient to define a biological function
(41). However, physiology has been based
on such functional analyses since its in-
ception. In our view, therefore, the most
adequate definition of physiology is a sci-
ence explaining functional organization.
If this characterization of physiology is
correct, then the strongest challenge to
this domain is not the appearance of
other experimental sciences but the re-
cent emergence of both non-functional
explanations and non-explanatory ap-
proaches in biology.
Non-Functional Explanations of
Biological Phenomena
Innovative approaches, such as systems
biology, have recently provided explana-
tions for biological phenomena that are
not functional in nature. If such non-
functional explanations are valid, then it
would be overstretching the mark to sug-
gest, as some have done, that systems
biology, in its entirety, is just a new incar-
nation of physiology.
Let us begin by considering one of the
many examples of a non-functional ex-
planation. The Gomperz-Makeham equa-
tion describes changes in the probability of
death over time in a living organism:
m共t兲 ⫽ I.eGt ⫹ E, where I is intrinsic vul-
nerability, G is the rate of aging, and E rep-
resents environmental risk. G has been
observed to be constant. Kowald recently
proposed a simplified systems biology hy-
pothesis concerning aging in which G is
expressed in terms of mathematical func-
tions describing the stochastic accumula-
tion of mitochondrial defects (62).
The explanandum (i.e., what is to be
explained) is the change in the probability
of death over time. The explanans (i.e.,
what the explanation is based on) is this
mathematical function expressing the
stochastic accumulation of defects. This
explanation must be considered “non-
functional” because it is not based on
biological functions. Indeed, physiologi-
cal functions, or at least their loss, instead
define the explanandum.
Table 2. Characterization of physiology on the basis of its method and object
Method Object
Physiology is: Physiology is the science of:
● An explanatory, as opposed to observational or predictive ● Normal and pathological phenomena
science
● The science of functional explanations of living phenomena ● The integrity of the organism
● A basic science into which all the results of other biological ● General phenomena common to many specialist
sciences must ultimately be translatable fields in biology

Philosophers have pointed out that sys-
tems biology sometimes resorts to expla-
nations of functions by an explanans that
is not itself a set of functions:
“In a first approximation, systems biol-
ogy may be said to study the interactions
between the components of biological
systems, and how they give rise to func-
tion and behavior by using a series of
‘omics’ operational protocols” (12).
Moreover, one of the aims of systems
biology is to decompartmentalize knowl-
edge about the interactions occurring
within physiologically defined systems
performing particular functions, to
achieve generalization to the interactions
of various components of various sys-
tems, as highlighted by the philosophers
O’Malley and Soyer (90). In this respect,
systems biology contrasts with physiol-
ogy, and with the major result of a long
physiological tradition: the “breaking up”
of the organism into well-delineated and
functional “apparatuses” or “systems.”
This tidy view of the concatenation of
compartmentalized functional systems
into a whole may, in some cases, hinder
understanding of how organisms work.
Along the same lines, the philosopher
Philippe Huneman provided several ex-
amples of explanations of robustness—an
essential property of biological systems at
several levels, but not a function—in
terms of topological properties (47). For
instance, scale-free networks, in which a
small number of nodes are highly con-
nected and large numbers of nodes are
poorly connected, are rarely disrupted by
random mutations, which have an equal
likelihood of striking any of the nodes of
the network (4).
Functional explanation is a crucial el-
ement in physiology. However, func-
tional explanations, although not
obsolete, naïve, or inadequate, are not the
only possible explanations applicable to
organisms. Non-functional explanations
also exist and are increasing in impor-
tance in modern biology.
Non-Explanatory Approaches in
Modern Biology
There has recently been an increase in
the use of approaches that do not seek
primarily to provide an explanation of the
phenomenon considered but rather to
predict and control it. This is particularly
true of approaches based on systems bi-
ology and computer models. One of the
many possible illustrations of this trend is
provided by research on cancer treat-
ments. In particular, “immunoscore,” ex-
pressing the degree of immune cell
infiltration into the tumor, has recently
been proposed as an alternative to the
traditional TNM score, based on the pres-
ence of cancer cells in the tumor (T) and
lymph node (N), and the presence of me-
tastasis (M) (2). The advocates of immu-
noscore use have claimed that this score
is superior to TNM for predicting disease
outcome and treatment response for
some cancers (37). This approach, which
is based on systems biology, the use of
complex computer models, bioinformat-
ics, and big data (36), does not seek ex-
planations in the way that physiology has
traditionally done. More generally, ap-
proaches focusing on prediction and con-
trol rather than explanation have rapidly
risen to the fore in many areas of biology
and medicine over the last 10 years. These
approaches can inspire, and be inspired
by, physiology, but are not themselves
physiological, in that they do not focus on
explanation.
Is Physiology the Basic Science of
Organisms?
In the eyes of many physiologists, non-
physiological scientific results, such as
those described above, acquire explan-
atory or predictive power only at the
expense of clarity. According to this
view, the findings of systems biology,
for example, become meaningful and
explanatory only when re-interpreted
physiologically. The general idea is that
systems biology provides tools for data
collection, whereas only physiology can
render the results intelligible. As Joyner
put it:
“. . . without a narrative approach
that includes hypothesis testing and
key concepts like homeostasis, systems
biology runs the risk of becoming sci-
entific ‘Abstract Expressionism’” (51).
According to the defenders of this
view, clarity can only be achieved by
placing the knowledge gathered in non-
physiological approaches into a frame-
work, by integrating it into a phy-
siological picture (52, 78, 79, 97). Without
this integration into a physiological
framework, biological claims cannot be
correctly understood and explained. This
is one of the implications of the notion
that physiology is an integrative science
and has been used to support the claim
that physiology should be seen as the ba-
sic science of organisms.
One argument that can be used in sup-
port of this view is that the functional
template provided by physiology is not
generally likely to be called into question
by the results of non-physiological
approaches. Indeed, in most cases, non-
physiological approaches do not provide
a novel functional explanation; they
merely provide more detail and fill in
gaps in our knowledge. This is what No-
ble calls the “boundary conditions” of the
higher level on the lower level (82), mean-
ing that results must be assimilated into a
template at the organism level, just as the
inner workings of ion channels cannot be
understood without looking at the bigger
picture of cell voltage.
However, we think that this argument
can be taken further since, in principle,

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there should always be a conceivable
functional explanation of the phenom-
enon considered. The real question,
therefore, is not so much whether phys-
iology is a basic science but whether it is
the basic science. The question thus
boils down to what we consider to be ulti-
mately clear or intelligible, which remains a
matter of debate. As pointed out above,
some would argue that systems biology
provides intelligibility through mathemati-
cal models rather than functional templates
(49), whereas others might claim that
chains of chemical reactions or an evolu-
tionary perspective also provide intelligibil-
ity without being based on function.
There is no reason a priori to suppose
that our understanding of what an organ-
ism does should necessarily involve the
interplay of functions, or for assuming
that anything the organism does could
not be understood in this way. Thus phys-
iology is indeed a basic science based on
a template of multiple layers of functions,
possibly encompassing all the knowledge
about organisms collected, but it is not
necessarily the basic science (i.e., the ul-
timate or most elementary science) in or-
ganism biology. As such, physiology is
neither timeless nor outdated, because its
descriptions of higher-level systems are
not necessarily final and can, in principle,
be modified in line with the results of
data-intensive biology, certain phenom-
ena may remain unexplained, and the de-
scriptions generated are relevant for the
organization of the information gener-
ated by this approach into a base of
knowledge.
Thus physiology is primarily defined
by a specific approach, a functional, ex-
planatory, and integrative approach. As
such, physiology is alive and well, but it
cannot be the all-encompassing disci-
pline that it once was. Over the last de-
cade, it has become increasingly clear
that physiology must coexist with other
approaches because it is not the only
way to explain phenomena and because
explanation need not be the sole goal of
biology.
Objects of Physiology
We will now turn our attention to defini-
tions of physiology based on its object of
investigation. What is the specific object
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of physiology, as opposed to other biolog-
ical sciences? What we refer to here as the
“object” of physiology is a highly general
property of living beings forming a dis-
tinctive focus of interest for physiology.
As reported in Table 2, this object has
been defined in the physiological litera-
ture as “normal” as opposed to “patho-
logical” processes, as the integrity of the
organism as a whole, and as universal or
quasi-universal biological processes, such
as homeostasis. Below, we consider these
three conceptions of the object of
physiology.
Physiology as the Science of
Physiological and Pathological
Phenomena
Physiology has sometimes been defined
as the science of healthy phenomena, and
sometimes as the science of both healthy
and pathological phenomena. This dis-
tinction, however, has been blurred by
the emergence of molecular biology. In-
deed, it is not always clear at the molec-
ular level whether a phenomenon is
“physiological” (normal) or “pathologi-
cal” (abnormal). It has been suggested
that this distinction is no longer relevant
to the general science of living organisms.
It has even been argued, by most philos-
ophers of medicine (14, 19, 32, 87), with
the notable exception of Christopher
Boorse and some of his followers (10, 46),
that this distinction is not grounded in
hard science but merely reflects our
values.
This argument may be robust, but it does
not necessarily imply that physiology has
FIGURE 1. Levels of explanation (explanandum and explananda)
Clinical phenomena (explandum) are first explained by physiological phenomena (explanans).
These physiological phenomena (explandum) can then be explained by molecular phenomena
(explanans) or by phenomena described by other innovative sciences.
become dispensable or is a remnant of the
past. Physiology remains a basic medical
and biological science. Rough physiological
descriptions of mechanisms serve as op-
erational and objective proxies for our in-
tuition that some states are “bad.” These
states may be considered to be natural-
ized clinical entities, in that they provide
a robust causal model of the basis for
clinical manifestations of disease (64).
When a molecular biologist scrutinizes
complex processes, such as cascades of
biochemical reactions, it is tacitly as-
sumed that these processes are involved
in physiological phenomena, pathological
phenomena, or both, in that they can be
causally linked to physiological or patho-
logical, that is, biological processes,
themselves known to underlie certain
states or behaviors. We know what hap-
pens during fever, cardiac insufficiency,
bronchial asthma, vomiting, diarrhea,
cramps, fainting, headaches, and so on,
although we do not always know why
these phenomena occur. In philosophical
terms, physiology is, in such cases, the
science of the explanandum of molecular
biology, that is, the prima facie biological
phenomenon to be explained, rather than
the science of the explanans, that is, the
underlying processes explaining the phe-
nomenon (see FIGURE 1).
Thus, as the science of the nonspecific
phenomena explaining the states we
deem normal or abnormal in daily life,
physiology plays a key role in describing
what requires further explanation, al-
though the explanation is often obtained
through other sciences, such as molecular level on the others (79). However, physi-
biology. ology is also “horizontally integrative,” in
that it compares and combines knowl-
Physiology as the Science of the edge accumulated in studies of different
Integrity of the Organism body components at the same level (16).
For example, physiology combines what
Physiology has often been described as
is known about the kidney, heart, and
the science of whole organisms (15, 53,
liver (organ level), or about different types
93). According to this view, rather than
of barriers in the body [such as the gut
being restricted to one particular biolog-
immune barrier and the blood-brain bar-
ical level or organ, physiology involves the
rier (25) (structure-type level), or about
study of biological phenomena across all
microglia in the brain and other phago-
levels. This implies that physiological
cytic cells in the body (cell level)]. It also
processes can occur at any level of orga-
involves studies of the ways in which dif-
nization in the organism, as testified by
the existence of subfields such as “cel- ferent body organs and subsystems inter-
lular physiology” (119) and “molecular act and are regulated, such as studies of
physiology” (88). It also implies that how the digestive, nervous, immune and
physiology is “integrative,” in that it endocrine systems communicate and
brings together knowledge accumulated influence each other (101), and how body
about different body compartments rhythms interact and are regulated (40).
(107). We suggest that physiology can be Many biologists (6, 65, 78, 96, 112) have
seen as “integrative” in two ways: “verti- highlighted the risks associated with try-
cally” and “horizontally” (FIGURE 2; see ing to explain biological phenomena with
also Ref. 117, p. 3). “analytic” or “reductive” methods, in
Physiology is “vertically integrative” in which the organism is broken down into
that it brings together knowledge about a isolated elements or subsystems. Most
given organ or system at different levels— physiologists avoid conflict between the
genes, proteins, cells, tissues, etc, (66, 82). study of “parts” and the “whole.” Instead,
For example, a physiological account of they suggest that physiology is “integra-
the functioning of the heart requires an tive” in that it combines and connects
understanding of the roles of the entities all the constituent parts of the organism
located at different levels (genes, pro- and all the biological processes occur-
teins, cells, tissues, etc.) in this function- ring within it. We feel that this “integra-
ing, and the potential influence of each tive” aim is still a key component of the
Organ Organ
Tissue Tissue
Vertical
integration
Cell Cell
Protein Protein
Gene Gene
Horizontal
integration
FIGURE 2. Physiology is both vertically (between different levels within an or-
gan) and horizontally (between different organs) integrative
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physiology of today (81, 82, 92, 98, 117)
but that it may not be as specific to
physiology as physiologists generally
claim. Systems biology, as we have al-
ready seen, also combines data from dif-
ferent levels and often adopts a holistic
perspective, without necessarily trying to
establish functional explanations be-
tween these components and levels in the
way that physiology does. Consequently,
physiology can still be seen as an integra-
tive discipline, but it can no longer be
considered the only integrative discipline.
It would, therefore, be inappropriate to
consider integration to be a feature
unique to physiology.
However, some physiologists go further
when considering the “integrity of the
organism.” They claim that the organism
is causally special, since the way in which
it is constructed and self-regulated ren-
ders it unique in the living world (15).
Commenting on the views of Claude Ber-
nard, Cannon explained how organisms
are unique: “as organisms become more
independent, freer from changes in the
outer world, they do so by preserving uni-
form their own inner world in spite of
shifts of outer circumstances.” This idea
was later taken up and refined by the
proponents of “autopoiesis” (68, 102).
The integrity of the organism is some-
times interpreted more specifically as re-
sulting from one particular biological
process or system, typically the nervous
(7, 15, 17, 18, 105) or immune (11, 73)
system. The nervous system integrates in-
formation originating from all body com-
ponents, controls a myriad of biological
processes, accounts for a very large pro-
portion of the energy consumed by the
body (100), and, in some circumstances,
is given priority over other body constit-
uents (94). The immune system consti-
tutes a mechanism of discrimination that
includes and excludes elements, thereby
making a decisive contribution to delin-
eation of the boundaries of the organism
and to the constant aggregation of its
constituents (99). Both the nervous and
the immune systems may play a unifying
role, and they may even do so in concert
via the complex neuroimmunoendocrine
system (44).
Are all these views still held in the phys-
iology of today? We think so. Many au-
thors stress the importance of taking the
241
whole organism into account in biologi-
cal and medical phenomena, and in in-
vestigations of the contributions of the
nervous and immune systems to organ-
ism integrity. For example, recent studies
have highlighted the control over many
metabolic processes wielded by the ner-
vous system (76), and the contribution of
the immune system, as a whole, to the
surveillance of anomalies in the organism
(61, 109). Moreover, these contributions
are often presented as “physiological”
(61), suggesting that traditional physio-
logical views about the nature of organ-
isms persist in some of the biological
disciplines that have arisen from physiol-
ogy (31).
Physiology as the Science of a
Highly General, Almost Universal,
Biological Process: The Case of
Homeostasis
Physiology has focused on phenomena
observable at all levels, in all living beings,
such as homeostasis in particular. Ho-
meostasis has played the role of a central,
all-encompassing phenomenon forming
the principal object of physiology: “ho-
meostasis is the process that gave birth to
physiology and continues to define it”
(Ref. 78; see also Refs. 20, 82, 106). This
term is still widely used today in physiol-
ogy and the biological domains that it has
spawned, such as neurosciences, immu-
nology, endocrinology, and stem cell bi-
ology (30, 39, 61, 67, 89). Other concepts,
such as stress, could be considered here,
but homeostasis has greater generality.
No precise description or assessment of
the extent of the phenomenon of homeo-
stasis is yet available. The first vague and
limited description of this phenomena
was humoralism, the ancient theory that
health results from a general balance be-
tween blood components. Claude Ber-
nard (7) converted this vague idea of
humoralism (i.e., a balance of components
in the blood) into a much more accurate
description under the label of “fixité du mi-
lieu intérieur,” defined as the active main-
tenance, in organisms, of certain values
within fixed boundaries (water, nutrients,
oxygen, salt, and, in some cases, tempera-
ture, etc.). Cannon gave homeostasis its
name and focused on the description of
physiological systems fulfilling the vari-
ous functions of stability, and on the
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concatenation of various mechanisms
resulting in stability. He also stressed
the notion of boundaries for fluctua-
tions and described other parameters
subject to homeostatic regulation, such
as glucose concentration and pH (15).
Wiener generalized the description of
homeostasis to all cybernetic systems
and introduced the notion of a feedback
loop (118): he pioneered a tradition in
mathematical biology that culminated
in the development of dynamic systems
theory between the 1960s and 1980s (9).
Since the 1980s, there has been much
discussion of new concepts thought to
expand the explanatory power of homeo-
stasis, such as “rheostasis” (75) and “al-
lostasis,” originally described by Sterling
and Eyer as a form of cognitive anticipa-
tion of potential changes in the environ-
ment, selected during evolution due to
the improvements in fitness it provides
(103, 104, 110, 111). The contribution of
these new concepts has been called into
question (27). More recently, attempts
have been made to redefine homeostasis
through comparison with the concept of
robustness (56 – 60). Homeostasis is a key
concept for understanding organisms,
and conceptual breakthroughs and em-
pirical discoveries about its various forms
and scope are still being made. The im-
perfect description and mapping of ho-
meostasis is sufficient to demonstrate the
potential vitality of physiology.
A further illustration of this vitality is
provided by the observation that many
newly discovered mechanisms are not ex-
ceptions to known instances of homeosta-
sis, instead being embedded in unexpected
forms of homeostasis, thereby extending
the scope of this concept. An example is
provided by studies of interactions between
the immune and neurological systems in
the onset of mental disorders (26, 33, 38). In
such studies, these interactions are seen as
constituting a deregulation of homeostatic
processes, the understanding of which
lies outside the traditional boundaries
of physiological systems. For instance,
physiological knowledge suggests that
the immune system should not interfere
with tryptophan catabolism. Accidental
interactions cannot be studied by tradi-
tional physiological approaches and
must therefore be studied by molecular
biology methods instead. In such cases,
homeostasis is background knowledge
and does not play a key role in
discovery.
In a second type of discovery, these in-
teractions are themselves described as a
new instance of homeostasis, calling into
question the original distinction between
systems. As the object of the investigation is
then a new homeostatic system, the discov-
ery legitimately counts as progress in
physiology. For instance, McEwen’s work
on “allostasis” proposes the integration of
cytokines into the normal, but enhanced
balance we generally call “stress” (69 –72).
McEwen and coworkers illustrate this idea
with the example of the “regulation” of pro-
and anti-inflammatory cytokines by gluco-
corticoids and catecholamines and the
“feedback” of peripheral IL-6 on central
IL-6, contribution to regulation of the
stress axis via the hippocampus. An-
other example is provided by the so-
called “neurovascular unit,” in which
neurons, astrocytes, smooth muscle
cells, and endothelial cells are involved
in the “homeostasis of the brain mi-
croenvironment” (48): instead of think-
ing of the neuronal network, circulatory
system, and neuroglia as generally sep-
arate coordinated systems, a neurovas-
cular unit is defined as a locally
regulated “functional unit” (48) acting
in coordination and competition with
other such neurovascular units.
Similarly, recent findings concerning
the intimate interactions and between the
nervous and immune systems and the
molecular pathways common to these
two systems (55, 91, 113) have led several
authors to propose the concept of a “neu-
roimmune unit” (115) or a “neuroim-
mune cell unit” (NICU) (116) based on
the general idea that “the nervous system
and immune system have evolved to work
in a concerted manner to promote tissue
homeostasis and defense” (116). Ongoing
discoveries about the dialog between the
microbiota (the microbes residing in and
on the host), the nervous system, and the
immune system provide strong support
for this view (35). Some have gone even
further, proposing the concept of a single
and encompassing “neuroendocrine-im-
mune system” (95), which is understood
to be the actual protector of homeostasis
in the organism.
 Discoveries of the first type may give
the impression that the study of interac-
tions extends beyond the limits of physi-
ology into a different branch of science,
because the explanations obtained are
not based on physiological and homeo-
stasis-related considerations. By contrast,
discoveries of the second type suggest
that, over and above what physiology has
already taught us, there are still physio-
logical phenomena to be discovered and
that homeostasis remains the best con-
ceptual framework in which to interpret
them.
Conclusions
So, is physiology dead or alive? Many dif-
ferent defining features have been attrib-
uted to physiology, and, depending on
the features considered, different answers
to this question may be obtained. Most of
these defining features have been inher-
ited from the centuries-long history of
this discipline. We propose here to distin-
guish between definitions of physiology
based on its method and definitions of
physiology based on its object.
In terms of its method, physiology is:
1) A quest to identify biological func-
tions in organisms. From this point
of view, physiology is one of many
explanatory sciences in biology, to
be contrasted, in particular, with
other biological sciences seeking
non-functional explanations.
2) A search for explanations based on
biological functions. From this point
of view, physiology is one of many
possible forms of biological science,
with others instead focusing on pre-
diction or manipulation.
3) A basic biological science but no
longer necessarily the basic biologi-
cal science.
In terms of its specific object, physiol-
ogy focuses on:
4) Physiological and pathological phe-
nomena, no longer as an explana-
tion for clinical phenomena but
described so that they can be ex-
plained (generally at a molecular
level): here, physiology is no longer
the central explanatory discipline
but is instead becoming the central
descriptive discipline.
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Copyright © 2018 American Physiological Society. All rights reserved.
5) The integrity of the organism, which
may now also be accounted for by
different, non-functional disciplines.
6) All-encompassing phenomena, such
as homeostasis, which, although not
able to account for all biological phe-
nomena, nevertheless provide useful
and fruitful models for discovering
new processes and understanding
them.
On balance, neither the method nor the
object of investigation of physiology is
outdated. What seems crucial today is to
acknowledge the existence of novel, wide-
ranging approaches, such as systems bi-
ology, and, rather than trying to reduce
them all to physiology, to construct a
fruitful dialog with them (85, 112). Physi-
ology will continue to survive, as it always
has, and can only be strengthened by ex-
changes with other fields from which it
can take inspiration. 䡲
We thank François Duchesneau, Jean Gayon,
and Michel Morange for extremely useful com-
ments on a previous version of the manuscript,
and Philippe Huneman, Denis Noble, and
Charles Wolfe for very stimulating discussions.
T.P. has received funding from the Europ-
ean Research Council (ERC) under the European
Union’s Horizon 2020 research and innovation
programme, grant agreement no. 637647-IDEM.
No conflicts of interest, financial or otherwise,
are declared by the author(s).
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